Annual Rheumatology & Therapeutics Review for Organizations & Societies

Annual Rheumatology & Therapeutics Review for Organizations & Societies

Update on Granulomatosis with Polyangiitis (Wegener s)

Learning Objectives Identify the clinical features of granulomatosis with polyangiitis (Wegener s)(gpa) Describe the diagnostic approach to GPA Outline the treatment options for GPA

Vasculitis = Inflammation of the Blood Vessel blood vessel damage compromise of vessel lumen attenuation of vessel wall organ ischemia aneurysm formation / hemorrhage Renal infarction Renal microaneurysms

Vasculitis Is Not One Specific Disease Primary Vasculitides Unique disease entities without a currently identified underlying cause where vasculitis forms the pathological basis of tissue injury Secondary Vasculitides Vasculitis occurring secondary to an underlying disease or exposure Giant cell arteritis Takayasu arteritis Kawasaki disease Polyarteritis nodosa Granulomatosis with polyangiitis (Wegener s) Microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) IgA vasculitis (Henoch-Schönlein) Medications Infection Malignancy Transplant Cryoglobulinemia Connective tissue disease (RA, SLE, myositis, Sjögren s) Jennette et al. A&R 2013; 65:1

Granulomatosis with Polyangiitis (Wegener s) (Formerly Wegener s Granulomatosis) Epidemiology Affects ~3 in 100,000 persons Male = female Mean age of onset 41-65 years (can occur at any age) Etiology No currently identified: - infectious or environmental trigger - genetic association Strong evidence that disease is immunologically mediated - data gathered within the laboratory - response to immunosuppressive treatment - inflammation seen on tissue histology

Granulomatosis with Polyangiitis (Wegener s) Characterized by: Histology: necrotizing granulomatous inflammation vasculitis of small to medium vessels Clinical predilection to involve: upper airways lungs kidneys

Granulomatosis with Polyangiitis (Wegener s) Upper Airway Involvement Occurs in ~95% of Patients

GPA (Wegener s) Pulmonary Involvement Occurs in ~ 85% of Patients

GPA (Wegener s) Glomerulonephritis (GN) 80% will have GN at some point 20% have GN at presentation can be rapidly progressive lacks symptoms proteinuria, active urine sediment Histology focal, segmental, crescentic, necrotizing GN few to no immune complexes (pauci-immune)

Granulomatosis with Polyangiitis (Wegener s) Ocular Involvement Occurs in 56 % Can affect any ocular structure and be visually threatening Scleritis / episcleritis Orbital disease

Granulomatosis with Polyangiitis (Wegener s) Cutaneous Involvement Occurs in 46% of Patients

Granulomatosis with Polyangiitis (Wegener s) Organ System Involvement in 158 Patients ENT LUNG KIDNEY JOINT EYE SKIN PNS CNS Onset Total HEART Hoffman et al. Ann Intern Med 1992 0 20 40 60 80 100 Percent of Patients

Granulomatosis with Polyangiitis (Wegener s) Differential Diagnosis infection neoplasm / lymphoproliferative disease connective tissue disease granulomatous disease other causes of glomerulonephritis (when present) Differentiation from GPA (Wegener s) is essential as the treatment is different in many instances Diagnosis is usually made by the presence of specific histologic features in a clinically compatible setting

QUESTION You are seeing a 33 year old male where GPA is suspected although infection remains a concern. He has sinus mucosal thickening, cavitary pulmonary nodules, nodular skin lesions, and a (+) panca. A biopsy of which of the following would provide the highest diagnostic yield for GPA? A. Sinus biopsy B. Lung biopsy by VATS C. Skin biopsy D. Biopsy is not needed as (+) panca has sufficient predictive value

Granulomatosis with Polyangiitis (Wegener s) Diagnosis - Biopsy Not all biopsies are diagnostic Presence of granulomas and/or vasculitis can be patchy Positive yield associated with the amount of tissue obtained ENT 21% sinus>nasal Lung 91% open lung biopsy 7% transbronchial biopsy Kidney Skin focal, segmental, necrotizing glomerulonephritis with few to no immune deposits (pauci-immune) usually insufficient evidence for diagnosis cutaneous vasculitis can be seen in many settings

Granulomatosis with Polyangiitis (Wegener s) Evaluation History Physical examination Radiographs Laboratories symptoms - presence and duration nasal membranes, eye, skin, joint, nerve CXR even in the absence of symptoms serum chemistries (renal function) CBC ESR Urinalysis - if (+) blood perform microscopy on fresh urine to look for casts ANCA

Antineutrophil Cytoplasmic Antibodies (ANCA) 1982 Davies et al. BMJ Observed serum antibodies that stained neutrophil cytoplasm in 8 patients with segmental necrotizing glomerulonephritis 1985 Van der Woude et al. Lancet Association between cytoplasmic staining antibodies and GPA (Wegener s) Antibodies were more frequently found in active (25 of 27) vs inactive (4 of 32) disease

Target antigens in GPA (Wegener s) Cytoplasmic canca = Proteinase-3 Ethanol Fixation = Myeloperoxidase panca Perinuclear

Methods of ANCA Testing Indirect Immunofluorescence canca panca Load Antigen Add Serum Antibody Add Antibody Enzyme Conjugate Add Enzyme Substrate ELISA (target antigen-specific) Proteinase 3 Myeloperoxidase Measure Optical Density

canca GPA (Wegener s) Microscopic polyangiitis EGPA (Churg-Strauss) Case reports of associations positive canca by IIF positive anti-pr3 ELISA positive canca by IIF negative anti-pr3 ELISA A (+) ANCA done by immunofluorescence should be confirmed by antigen-specific (PR3, MPO) ELISA panca GPA (Wegener s) Microscopic polyangiitis EGPA (Churg-Strauss) Idiopathic crescentic GN Inflammatory bowel disease Other autoimmune diseases Infection Drugs positive panca by IIF positive anti-mpo by ELISA positive panca by IIF negative anti-mpo by ELISA

canca panca (-) ANCA GPA (Wegener s) 75-90% 5-20% up to 20% Question: Can (+) ANCA be used to diagnose GPA in place of a tissue biopsy? It depends upon the likelihood of disease based upon the clinical scenario Influenced by GPA (Wegener s) being uncommon and treatment toxicity sinus, lung, renal disease predictive value 90% sinus and lung disease predictive value of ANCA ~30-60% remains a high potential of infection/neoplasm (+) ANCA has poor positive predictive value in low prevalence populations Diagnosis by biopsy remains necessary in many instances

QUESTION You are seeing a 45 year old male with GPA on methotrexate and prednisone 20 mg/day who was hospitalized for cough and fever. He has new B/L interstitial infiltrates on chest CT. The medical team checked an ANCA and this is markedly higher than previously. Which of the following statements is true? A. This is not Pneumocystis as this does not occur with methotrexate B. Methotrexate pneumonitis should be considered C. This is a disease relapse as his ANCA has risen D. PFTs with DLCO will not be useful in this setting

Is ANCA a Reliable Measure of Disease Activity? In an individual person ANCA level often varies In large series, patients with active vs inactive disease: were more frequently ANCA (+) had higher titers of ANCA Question: can ANCA be used to predict relapse and guide treatment?

ANCA - Utility in Guiding Treatment Kerr et al. Arthritis & Rheum 1994; Boomsma et al. Arthritis & Rheum 2000 43% with a 4 fold rise in titer did not relapse Finkielman JD, et al. Ann Intern Med 2007;147:611 156 patients with GPA (Wegener s) ANCA levels were only weakly associated with disease activity Changes in ANCA levels explained < 10% of the variation in disease activity Decreases in ANCA levels were not associated with shorter time to remission Increases in ANCA levels were not associated with relapse 43% relapsed within 1 year of an increase in ANCA levels ANCA titers do not correlate well with disease activity and should not be used to guide immunosuppressive therapy

Treatment of Granulomatosis with Polyangiitis (Wegener s) Patient survival What are the goals of treatment? Induce remission of active disease Remission - absence of disease activity Avoid disease relapse Relapse - return of disease activity after remission Minimize therapeutic toxicity

Treatment of Granulomatosis with Polyangiitis (Wegener s) Untreated disease Walton 1958: median survival time 5 months Glucocorticoids alone Hollander & Manning 1967: median survival time 12.5 months Daily cyclophosphamide and prednisone Fauci & Wolff 1973: remission in 12 / 14 patients Hoffman et al 1992: 75% complete remission 90% improvement 80% survival

GPA Effective Treatment New Challenges Relapse Occurs in 50-70% of patients May be similar or different from initial presentation Treatment Toxicity Complications of Cyclophosphamide Infection 46% Bladder injury Hemocytopenias Infertility Myelodysplasia Transitional cell carcinoma Complications of Glucocorticoids Damage Can occur as a result of disease or treatment Continues to accumulate over time Can be difficult to differentiate from active disease

GPA - Induction-Maintenance Staged Treatment Approaches Active Disease Remission (3-6 months) Maintain Remission Induction Maintenance Cyclophosphamide Methotrexate Cyclophosphamide Cyclophosphamide Azathioprine Mycophenolate mofetil

QUESTION A 65 year old female with GPA has been on cyclophosphamide for 3 months and is ready to switch to a maintenance option. Her creatinine is 2.3 mg/dl, urinalysis is negative for blood with trace protein, chest CT shows significant improvement but not complete resolution of the prior pulmonary nodules. Which of the following would you recommend she be switched to? A. Azathioprine B. Mycophenolate mofetil C. Methotrexate D. Rituximab

GPA - Induction-Maintenance Staged Treatment Approaches Active Disease Remission (3-6 months) Maintain Remission Induction Maintenance Cyclophosphamide Cyclophosphamide Cyclophosphamide Methotrexate Azathioprine Mycophenolate mofetil Langford et al. A&R 1999 Reinhold-Keller et al, 2002 Jayne et al, NEJM 2003 Heimstra et al, 2010 Langford et al, A&R 2004 Pagnoux et al, NEJM 2010 Methotrexate vs Azathioprine similar rates of toxicity and relapse Azathioprine vs Mycophenolate MMF may have a higher rate of relapse

Daily versus IV Cyclophosphamide for Remission Induction degroot et al. Ann Int Med 2009;150:670, Harper et al. Ann Rh Dis 2012;71:955 Daily IV OR 15 mg/kg q 2 wks x 3 doses 2 mg/kg 1.5 mg/kg 15 mg/kg Every 3 weeks Azathioprine 2mg/kg/d Azathioprine 2mg/kg/d Prednisolone Remission Induction Consolidation Phase 0 3 6 // Months 18 149 patients Time to remission: IV=PO, median 3 mo Long term relapse: IV 40% PO 21% (p=0.03) Total CYC dose: IV < PO (similar at 3 mo) Leukopenia: IV < PO (PO after mo 2) Issues to consider Consolidation phase CBC frequency (wbc drops over time) IV days 10, 14, before pulse; PO QW x 1 mo, QOW x 1 mo, then monthly IV CYC - effective but not superior to daily CYC higher relapse rate When using PO CYC aim for 3-4 months, with q 1-2 week CBC

QUESTION A 55 year old female was just diagnosed with GPA with sinus disease, migratory arthralgias, three 1x2cm pulmonary nodules without respiratory compromise, (+) PR3-cANCA, lung biopsy showing granulomatous vasculitis. Her urinalysis and creatinine are normal. During your overall discussion of treatment, you learn she is extremely fearful of rituximab. Which of the following would you recommend she be treated with? A. Prednisone alone B. Prednisone and cyclophosphamide C. Prednisone and methotrexate D. Prednisone and azathioprine

GPA Recognition of the Spectrum of Disease Severity Severe Non-Severe Alveolar hemorrhage Glomerulonephritis CNS Mononeuritis multiplex Pericarditis Vision threatening scleritis Influences treatment decisions Sinonasal disease Oral mucosa Skin Conductive hearing loss Musculoskeletal Lung no respiratory compromise Cyclophosphamide or rituximab Methotrexate

Methotrexate for Remission Induction of Non-Severe degroot Disease et al. Arthritis Rheum 2005;52:2461 Cyclophosphamide 2 mg/kg/d 15mg/wk Cyclophosphamide 1.5 mg/kg/d OR Methotrexate 20-25mg/week Prednisolone Remission Months 0 3 6 10 12 100 patients Induction of remission within 6 months Methotrexate 90% Cyclophosphamide 93% Methotrexate is not inferior to cyclophosphamide for remission induction of non-severe disease

Treatment of Granulomatosis with Polyangiitis (Wegener s) What about Biologic Agents? Specific immunologic targeting may: reduce toxicity reduce relapse induce remission Specific targeting may be insufficient Unexpected effects on disease Disease-specific toxicities Investigation of specific agents has been guided by hypotheses regarding pathophysiologic mechanisms

Use of Etanercept in GPA (Wegener s) Standard Therapy + Randomization Induction Prednisone with taper Etanercept Placebo Maintenance 0 3 6 // Close of trial 180 patients Objective: determine the efficacy of etanercept to sustain remission Sustained remission > 6 months etanercept 69.7% placebo 75.3% P=0.39 Does not support the use of etanercept in the treatment of GPA Wegener s Granulomatosis Etanercept Trial (WGET), NEJM 2005; 352:19

Cyclophosphamide vs Rituximab for Stone et al. NEJM 2010; 363:221 Remission Induction (RAVE) Cyclophosphamide Azathioprine OR (Blinded) Rituximab (375mg/M2/week x 4 weeks) Prednisone Significant exclusions: - creatinine > 4.0 mg/dl - mechanical ventilation 0 6 // 18 Months Primary Endpoint = in remission and off prednisone at 6 months 197 ANCA (+) GPA or MPA Rate of adverse events: RTX = CYC Meeting primary endpoint All patients: RTX 64%, CYC 53% (p<0.001) Relapsing patients: RTX 67%, CYC 42% Severe relapse: RTX 6%, CYC 10% Mortality rate: 2% (1 RTX, 2 CYC) For remission induction, rituximab is as effective as cyclophosphamide This was the basis for FDA approval of RTX for GPA/MPA in April 2011

CYC vs Rituximab for Remission Induction Jones et al. NEJM 2010; 363:211 (RITUXVAS) CYC IV CYC Prednisolone Azathioprine VERSUS RANDOMIZED 3:1 RTX:CYC-AZA (Non-Blinded) Rituximab (375mg/M2/week x 4 weeks) RTX IV CYC x 2 Prednisolone 0 6 // 24 Months Primary Endpoint = sustained remission (BVAS=0 for 6 months) 44 ANCA (+) patients, new dx Rate of adverse events: RTX = CYC Hypothesis: RTX better than CYC Primary endpoint: RTX 76%, CYC 82% Mortality rate: 18% (6 RTX, 2 CYC) - Median age 68, 20% dialysis - GFR: RTX 20, CYC 12 ml/min Rituximab was effective but was not superior to cyclophosphamide

Rituximab (RTX) in GPA Remission induction Question Rituximab is as effective as cyclophosphamide for remission induction of severe disease does that mean it should be used to induce remission in everyone? No there is not strong data for use in all populations Relapsing severe disease Newly diagnosed severe disease Non-severe relapse, occurring on methotrexate Non-severe relapse, never received methotrexate Newly diagnosed non-severe disease Fulminant disease (creatinine > 4.0, mechanical ventilation) Strength of evidence for use Strong Weak

Probability of Remaining in Complete Remission Rituximab (RTX) in GPA Rituximab induces remission So what happens after rituximab? Specks U et al. N Engl J Med 2013; 369:417 No difference in RTX vs CYC/AZA 30% relapse within 1 year 1.0 0.8 0.6 Relapses occur after rituximab so a plan for remission maintenance needs to be considered in each patient 0.4 0.2 0.0 0 P = 0.76 CYC/AZA (n=70) RTX (n=76) Options Close clinical observation and retreat with rituximab for relapse Conventional maintenance agent (MTX, AZA, MMF) Scheduled repeat rituximab infusions 100 200 300 400 Time from Complete Remission to Relapse (days) At the current time the optimal approach to maintenance after rituximab has not been determined

GPA (Wegener s) - Current Treatment Remission Induction (3-6 months) Maintenance (at least 2 years) Severe Disease Cyclophosphamide + GC Methotrexate Azathioprine (Mycophenolate mofetil) Rituximab + GC Non-severe Disease Methotrexate + GC Methotrexate Factors to take in consideration in determining treatment: Level of disease severity Medication contraindications Initial disease or relapse Past treatment history

Summary GPA (Wegener s) Multi-system disease characterized by: small/medium vasculitis of the lungs, kidneys, nerve, skin necrotizing, granulomatous inflammation crescentic glomerulonephritis with few to no immune complexes frequent presence of circulating ANCA Since the introduction of effective treatment: opportunity for long term survival and follow-up recognition of relapse frequency and medication side effects exploration of immunologic mechanisms Questions for the future: why do we see this pattern of organ involvement? different tissues respond individually to injury and treatment why? are there triggers for disease and relapse? can treatment strategies be individualized based on these?